Process for the preparation of a solid, orally administrable pharmaceutical composition

ABSTRACT

The present invention relates to a process for the preparation of a solid, orally administrable pharmaceutical composition, comprising 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidin-5-yl}-methyl)-2-thiophenecarboxamide in hydrophilized form, and its use for the prophylaxis and/or treatment of diseases.

The present invention relates to a process for the preparation of asolid, orally administrable pharmaceutical composition, comprising5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidin-5-yl}-methyl)-2-thiophenecarboxamidein hydrophilized form, and its use for the prophylaxis and/or treatmentof diseases.

5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidin-5-yl}-methyl)-2-thiophenecarboxamide(I) is a low molecular weight, orally administrable inhibitor of bloodclotting factor Xa, which can be employed for the prophylaxis and/ortreatment of various thromboembolic diseases (for this see WO-A01/47919, whose disclosure is hereby included by way of reference). If,below, the discussion is of the active compound (I), all modificationsof5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidin-5-yl}-methyl)-2-thiophenecarboxamide(I), and the respective hydrates are additionally included.

The active compound (I) has a relatively poor water solubility (about 7mg/l). As a result of this, difficulties with the oral bioavailabilityand an increased biological variability of the absorption rate canresult.

To increase the oral bioavailability, various concepts have beendescribed in the past:

Thus, solutions of active compounds are frequently used which can befilled, for example, into soft gelatine capsules. On account of the poorsolubility of the active compound (I) in the solvents used for thispurpose, this option is not applicable, however, in the present case,since, in the necessary dose strength, capsule sizes would result whichare no longer swallowable.

An alternative process is the amorphization of the active compound.Here, the solution method proves problematical, since the activecompound (I) is also poorly soluble in pharmaceutically acceptablesolvents such as ethanol or acetone. Amorphization of the activecompound by means of the fusion method is also disadvantageous becauseof the high melting point of the active compound (about 230° C.), sincean undesirably high proportion of breakdown components is formed duringthe preparation.

Furthermore, a process for the hydrophilization of hydrophobic activecompounds as exemplified by hexobarbital and phenytoin has beendescribed (Lerk, Lagas, Fell, Nauta, Journal of Pharmaceutical SciencesVol. 67, No. 7, July 1978, 935-939: “Effect of Hydrophilization ofHydrophobic Drugs on Release Rate from Capsules”; Lerk, Lagas,Lie-A-Huen, Broersma, Zuurman, Journal of Pharmaceutical Sciences Vol.68, No. 5, May 1979, 634-638: “In Vitro and In Vivo Availability ofHydrophilized Phenytoin from Capsules”). The active compound particlesare blended here in a mixer with a methyl- or hydroxyethylcellulosesolution with extensive avoidance of an agglomeration step and thendried. The active compound thus obtained is subsequently filled intohard gelatine capsules without further treatment.

Surprisingly, it has now been found that a special treatment of thesurface of the active compound (I) in the course of the moistgranulation brings about improved absorption behaviour. The use of theactive compound (I) in hydrophilized form in the preparation of solid,orally administrable pharmaceutical compositions leads to a significantincrease in the bioavailability of the formulation thus obtained.

The present invention relates to a process for the preparation of asolid, orally administrable pharmaceutical composition comprising5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidin-5-yl}-methyl)-2-thiophenecarboxamidein hydrophilized form, in which

-   (a) first granules comprising the active compound (I) in    hydrophilized form are prepared by moist granulation-   (b) and the granules are then converted into the pharmaceutical    composition, if appropriate with addition of pharmaceutically    suitable additives.

The moist granulation in process step (a) can be carried out in a mixer(=mixer granulation) or in a fluidized bed fluidized bed granulation);fluidized bed granulation is preferred.

In the moist granulation, the active compound (I) can either beintroduced into the pre-mixture (original mixture) as a solid or it issuspended in the granulating liquid. Preferably, the active compound (I)suspended in the granulating liquid is introduced into the moistgranulation (suspension process).

In a preferred embodiment of the present invention, the active compound(I) is employed in crystalline form.

In a particularly preferred embodiment of the present invention, thecrystalline active compound (I) is employed in micronized form. Theactive compound (I) in this case preferably has an average particle sizeX₅₀ of less than 10 μm, in particular between 1 and 8 μm, and X₉₀ (90%proportion) of less than 20 μm, in particular of less than 15 μm.

The granulating liquid used according to the invention contains asolvent, a hydrophilic binding agent and, if appropriate, a wettingagent. The hydrophilic binding agent is in this case dispersed in thegranulating liquid or preferably dissolved therein.

The solvents used for the granulating liquid can be organic solvents,such as, for example, ethanol or acetone, or water or mixtures thereof.Preferably, water is used as a solvent.

The hydrophilic binding agents employed for the granulating liquid arepharmaceutically suitable hydrophilic additives, preferably those whichdissolve in the solvent of the granulating liquid.

Preferably, hydrophilic polymers such as, for example,hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (sodium andcalcium salts), ethylcellulose, methylcellulose, hydroxyethylcellulose,ethylhydroxyethylcellulose, hydroxypropylcellulose (HPC), L-HPC(low-substituted HPC), polyvinylpyrrolidone, polyvinyl alcohol, polymersof acrylic acid and its salts, vinylpyrrolidone-vinyl acetate copolymers(for example Kollidon® VA64, BASF), gelatine, guar gum, partiallyhydrolysed starch, alginates or xanthan are employed here. Particularlypreferably, HPMC is employed as a hydrophilic binding agent.

The hydrophilic binding agent can be present here in a concentration of1 to 15% (based on the total mass of the pharmaceutical composition),preferably of 1 to 8%.

The optionally present wetting agents employed for the granulatingliquid are pharmaceutically suitable wetting agents (surfactants). Thefollowing may be mentioned, for example:

sodium salts of fatty alcohol sulphates such as sodium lauryl sulphate,sulphosuccinates such as sodium dioctyl sulphosuccinate, partial fattyacid esters of polyhydric alcohols such as glycerol monostearate,partial fatty acid esters of sorbitan such as sorbitan monolaurate,partial fatty acid esters of polyhydroxyethylenesorbitan such aspolyethylene glycol sorbitan monolaurate, monostearate or monooleate,polyhydroxyethylene fatty alcohol ethers, polyhydroxyethylene fatty acidesters, ethylene oxide-propylene oxide block copolymers (Pluronic®) orethoxylated triglycerides. Preferably, sodium lauryl sulphate isemployed as a wetting agent.

If required, the wetting agent is employed in a concentration of 0.1 to5% (based on the total mass of the pharmaceutical composition),preferably of 0.1 to 2%.

In the pre-mixture (original mixture) of the moist granulation, furtherpharmaceutically suitable additives are present. The following may bementioned, for example:

-   -   fillers and dry binding agents such as cellulose powder,        microcrystalline cellulose, silicified microcrystalline        cellulose, dicalcium phosphate, tricalcium phosphate, magnesium        trisilicate, mannitol, maltitol, sorbitol, xylitol, lactose        (anhydrous or as a hydrate, for example monohydrate), dextrose,        maltose, sucrose, glucose, fructose or maltodextrins    -   disintegration promoters (disintegrants) such as        carboxymethylcellulose, croscarmellose (crosslinked        carboxymethylcellulose), crospovidone (crosslinked        polyvinylpyrrolidone), L-HPC (low-substituted        hydroxypropylcellulose), sodium carboxymethyl starch, sodium        glycolate of potato starch, partially hydrolysed starch, wheat        starch, maize starch, rice starch or potato starch

In the case of tablet formulations having modified (delayed) release ofactive compound, instead of the disintegration promoter (disintegrant)substances can be present which influence the release rate. Thefollowing may be mentioned, for example: hydroxypropylcellulose,hydroxypropyl-methylcellulose, methylcellulose, ethylcellulose,carboxymethylcellulose, galactomannan, xanthan, glycerides, waxes,acrylic and/or methacrylic acid ester copolymers with trimethylammoniummethylacrylate, copolymers of dimethylaminomethacrylic acid and neutralmethacrylic acid esters, polymers of methacrylic acid or methacrylicacid esters, ethyl acrylate-methyl methacrylate copolymers ormethacrylic acid-methyl acrylate copolymers.

The granules obtained in process step (a) are subsequently convertedinto the pharmaceutical composition according to the invention inprocess step (b).

Process step (b) comprises, for example, tabletting, filling intocapsules, preferably hard gelatine capsules, or filling as sachets, ineach case according to customary methods familiar to the person skilledin the art, if appropriate with addition of further pharmaceuticallysuitable additives.

Pharmaceutically suitable additives which may be mentioned are, forexample:

-   -   lubricants, glidants, flow regulating agents such as fumaric        acid, stearic acid, magnesium stearate, calcium stearate, sodium        stearyl fumarate, higher molecular weight fatty alcohols,        polyethylene glycols, starch (wheat, rice, maize or potato        starch), talc, highly disperse (colloidal) silica, magnesium        oxide, magnesium carbonate or calcium silicate    -   disintegration promoters (disintegrants) such as        carboxymethylcellulose, croscarmellose (crosslinked        carboxymethylcellulose), crospovidone (crosslinked        polyvinylpyrrolidone), L-HPC (low-substituted        hydroxypropylcellulose), sodium carboxymethyl starch, partially        hydrolysed starch, wheat starch, maize starch, rice starch or        potato starch

The present invention further relates to a solid, orally administrablepharmaceutical composition, comprising5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidin-5-yl}-methyl)-2-thiophenecarboxamide(I) in hydrophilized form.

The solid, orally administrable pharmaceutical composition according tothe invention by way of example and preferably comprises granules, hardgelatine capsules or sachets filled with granules, and tablets releasingthe active compound (I) rapidly or in a modified (delayed) manner.Tablets are preferred, in particular tablets rapidly releasing theactive compound (I). In the context of the present invention,rapid-release tablets are in particular those which, according to theUSP release method using apparatus 2 (paddle), such as described in theexperimental section in chapter 5.2.2., have a Q value (30 minutes) of75%.

The active compound (I) can be present in the pharmaceutical compositionaccording to the invention in a concentration of 0.1 to 60%, preferablyin a concentration of 1 to 40%, based on the total mass of theformulation. Here, the dose of the active compound (I) is preferably 1to 100 mg.

If appropriate, the granules of tablets according to the invention arecoated in a further step under customary conditions familiar to theperson skilled in the art. The coating is carried out with addition ofcustomary coating and film-forming agents familiar to the person skilledin the art, such as hydroxypropylcellulose,hydroxypropylmethylcellulose, ethylcellulose, polyvinyl-pyrrolidone,vinylpyrrolidone-vinyl acetate copolymers (for example Kollidon® VA64,BASF), shellac, acrylic and/or methacrylic acid ester copolymers withtrimethylammonium methylacrylate, copolymers of dimethylaminomethacrylicacid and neutral methacrylic acid esters, polymers of methacrylic acidor methacrylic acid esters, ethyl acrylate-methyl methacrylatecopolymers, methacrylic acid-methyl acrylate copolymers, propyleneglycol, polyethylene glycol, glycerol triacetate, triethyl citrateand/or colour additives/pigments such as, for example, titanium dioxide,iron oxide, indigotin or suitable colour lakes.

The present invention further relates to the use of the pharmaceuticalcomposition according to the invention for the prophylaxis and/ortreatment of diseases, in particular of thromboembolic diseases such ascardiac infarct, angina pectoris (including unstable angina),reocclusions and restenoses after an angioplasty or aortocoronarybypass, cerebral infarct, transitory ischemic attacks, peripheralarterial occlusive diseases, pulmonary embolisms or deep venousthromboses.

The invention is illustrated in greater detail below by means ofpreferred exemplary embodiments, to which, however, it is notrestricted. If not stated otherwise, all quantitative data below relateto percentages by weight.

EXPERIMENTAL SECTION 1. Tablet Preparation Using Granules Comprising theActive Compound (1) in Hydrophilized Form/Fluidized Bed GranulationProcess

1.1 Tablet Composition (in Mg/Tablet)

Active compound (I), micronized 20.0 mg Microcrystalline cellulose 35.0mg Lactose monohydrate 22.9 mg Croscarmellose (Ac-Di-Sol ®, FMC) 3.0 mgHydroxypropylmethylcellulose, 5 cp 3.0 mg Sodium lauryl sulphate 0.5 mgMagnesium stearate 0.6 mg Hydroxypropylmethylcellulose, 15 cp 1.5 mgPolyethylene glycol 3.350 0.5 mg Titanium dioxide 0.5 mg 87.5 mg

1.2 Preparation

Hydroxypropylmethylcellulose (5 cp) and sodium lauryl sulphate aredissolved in water. The micronized active compound (I) is suspended inthis solution. The suspension thus prepared is sprayed onto the originalmixture of microcrystalline cellulose, lactose monohydrate andcroscarmellose as a granulating liquid in the course of a fluidized bedgranulation. After drying and sieving (0.8 mm mesh width) the resultinggranules, magnesium stearate is added and mixed. The press-ready mixturethus obtained is compressed to give tablets having a 6 mm diameter and afracture resistance of 50-100 N. The subsequent coating of the tabletsis carried out using titanium dioxide, which is suspended in an aqueoussolution of hydroxypropylmethylcellulose (15 cp) and polyethyleneglycol.

2. Tablet Preparation Using Granules Comprising the Active Compound (1)in Hydrophilized Form/High-Speed Granulation Process

2.1 Tablet Composition (in Mg/Tablet)

Active compound (I), micronized 5.0 mg Microcrystalline cellulose 40.0mg Lactose monohydrate 33.9 mg Croscarmellose (Ac-Di-Sol ®, FMC) 3.0 mgHydroxypropylmethylcellulose, 3 cp 2.0 mg Sodium lauryl sulphate 0.5 mgMagnesium stearate 0.6 mg Hydroxypropylmethylcellulose, 15 cp 1.5 mgPolyethylene glycol 400 0.5 mg Iron yellow 0.1 mg Titanium dioxide 0.4mg 87.5 mg

2.2 Preparation

The substances cellulose, lactose monohydrate and croscarmelloseemployed are mixed in a high-speed mixer (original granule mixture).Hydroxypropylmethylcellulose (3 cp) and sodium lauryl sulphate aredissolved in water. The micronized active compound (I) is suspended inthis solution. The suspension thus prepared is added to the originalgranule mixture as a granulating liquid and blended uniformly with theoriginal granule mixture with the aid of the rapidly rotating stirrer.After thorough mixing has been carried out, the moist granules aresieved (4 mm mesh width) and dried in the fluidized bed. After sievingthe dried granules (0.8 mm mesh width), magnesium stearate is added andmixed. The press-ready mixture thus obtained is compressed to givetablets having a 6 mm diameter and a fracture resistance of 50-100 N.The subsequent coating of the tablets is carried out using titaniumdioxide and iron yellow, the pigments being suspended beforehand in anaqueous solution of hydroxypropylmethylcellulose (15 cp) andpolyethylene glycol.

3. Preparation of Granules Comprising the Active Compound (1) inHydrophilized Form and Filling as Sachets

3.1 Granule Composition (in mg/Sachet)

Active compound (I), micronized 50.0 mg Mannitol 662.0 mg Croscarmellose(Ac-Di-Sol ®, FMC) 15.0 mg Hydroxypropylmethylcellulose, 5 cp 15.0 mgSodium lauryl sulphate 1.0 mg Highly disperse silica (Aerosil ® 200,Degussa) 2.0 mg Strawberry flavouring, spray-dried 5.0 mg 750.0 mg

3.2 Preparation

Hydroxypropylmethylcellulose (5 cp) and sodium lauryl sulphate aredissolved in water. The micronized active compound (I) is suspended inthis solution. The suspension thus prepared is sprayed onto the originalmixture of mannitol and croscarmellose as a granulating liquid in thecourse of a fluidized bed granulation. After drying and sieving (0.8 mmmesh width) the resulting granules, highly disperse silica (Aerosil®)and strawberry flavouring are added and mixed. The mixture thus obtainedis filled into sachet pouches to 750 mg with the aid of a sachet fillingmachine.

4. Preparation of Granules Comprising the Active Compound (1) inHydrophilized Form and Filling into Hard Gelatine Capsules

4.1 Granule Composition (in mg/Capsule)

Active compound (I), micronized 20.0 mg Microcrystalline cellulose 30.0mg Lactose monohydrate 79.5 mg Maize starch 25.0 mgHydroxypropylmethylcellulose, 5 cp 4.5 mg Sodium lauryl sulphate 0.5 mgHighly disperse silica (Aerosil ® 200, Degussa) 0.5 mg 160.0 mg

4.2 Preparation

Hydroxypropylmethylcellulose (5 cp) and sodium lauryl sulphate aredissolved in water. The micronized active compound (I) is suspended inthis solution. The suspension thus prepared is sprayed onto the originalmixture of microcrystalline cellulose, lactose monohydrate and maizestarch as a granulating liquid in the course of a fluidized bedgranulation. After drying and sieving (0.8 mm mesh width) the resultinggranules, highly disperse silica (Aerosil®) is added and mixed. Themixture obtained is filled to 160 mg in each case into hard gelatinecapsules of capsule size 2.

5. Comparison of Tablets with/without Hydrophilized Active Compound (I)

5.1 Tablet Composition, Preparation

in order to investigate the tablet properties and the improvedbioavailability of formulations containing hydrophilized active compound(I), uncoated tablets having a 10 mg active compound content (I) of thefollowing composition are prepared (in mg/tablet):

Active compound (I), micronized 10.0 mg Microcrystalline cellulose 40.0mg Lactose monohydrate 27.9 mg Croscarmellose (Ac-Di-Sol ®, FMC) 3.0 mgHydroxypropylmethylcellulose, 5 cp 3.0 mg Sodium lauryl sulphate 0.5 mgMagnesium stearate 0.6 mg 85.0 mg

Tablet A: prepared by direct tabletting without granulation

Tablet B: prepared by the fluidized bed granulation/suspension processdescribed in 1.2

The mixture for tablet A and the granules for tablet B are in each casepressed to give tablets having a diameter of 6 rum and a fracturestrength of about 70-80 N.

5.2 Tablet Properties

5.2.1 Disintegration Time in Water (USP Disintegration Tester, Erweka):

-   -   Tablet A: about 1.5 minutes    -   Tablet B: about 6.5 minutes

5.2.2 In-Vitro Release

The amounts of active compound released based on the declared totalcontent of the tablets are shown in Table 1 below:

TABLE 1 In-vitro release 15 min 30 min 45 min 60 min Tablet A 87% 92%93% 94% Tablet B 94% 95% 96% 96%

(USP paddle, 900 ml of acetate buffer pH 4.5+0.5% sodium laurylsulphate, 75 rpm)

5.2.3 Bioavailability

For the investigation of the bioavailability, three dogs were in eachcase administered three tablets of A or three tablets of B in cross-overfashion. The corresponding pharmacokinetic parameters after oraladministration of 3 mg of active compound (I)/kg are listed in Table 2below:

TABLE 2 Pharmacokinetic parameters of active compound (I) Animal MeanS.D. Mean S.D. 1 2 3 geom. geom. arithm. arithm. Tablet A AUC(0-24) [mg· h/l] 1.39 2.31 3.34 2.21 1.55 2.35 0.974 AUC(0-24)_(norm) [kg · h/l]0.464 0.770 1.11 0.735 1.55 0.782 0.325 C_(max) [mg/l] 0.299 0.398 0.4300.371 1.21 0.376 0.0684 C_(max, norm) [kg/l] 0.0997 0.133 0.143 0.1241.21 0.125 0.0228 C(24)/C_(max) [%] 12.2 2.99 55.1 12.6 4.29 23.4 27.8t_(max) [h] 1.00 1.50 0.750 1.04 1.42 1.08 0.382 Tablet B AUC(0-24) [mg· h/l] 2.82 3.03 3.73 3.17 1.16 3.19 0.476 AUC(0-24)_(norm) [kg · h/l]0.938 1.01 1.24 1.06 1.16 1.06 0.159 C_(max) [mg/l] 0.478 0.513 0.3210.428 1.29 0.437 0.102 C_(max, norm) [kg/l] 0.159 0.171 0.107 0.143 1.290.146 0.0341 C(24)/C_(max) [%] 26.4 1.17 93.4 14.2 9.53 40.3 47.7t_(max) [h] 1.00 1.50 0.750 1.04 1.42 1.08 0.382

Result: In spite of slower disintegration (see 5.2.1) and very similarin-vitro release (see 5.2.2) of tablet B in comparison to tablet A,tablet B has marked advantages in absorption and thus a bioavailabilityincreased by about 35%. At the same time, a marked decrease in thevariability is to be noted. The only difference between tablet A andtablet B is the hydrophilization of the active compound (I) in tablet Bwith the aid of the suspension process in the course of the moistgranulation.

1. A process for the preparation of a solid, orally administrablepharmaceutical composition comprising5-chloro-N-({5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidin-5-yl}-methyl)-2-thiophenecarboxamide(I) in hydrophilized form, comprising the following steps: (a) firstpreparing granules comprising the active compound (I) in hydrophilizedform by moist granulation (b) and converting the granules into thepharmaceutical composition, if appropriate with addition ofpharmaceutically suitable additives.
 2. The process according to claim1, wherein the moist granulation method used is fluidized bedgranulation.
 3. The process according to claim 1, wherein the activecompound (I) is employed in crystalline form.
 4. The process accordingto claim 3, wherein the active compound (I) is employed in micronizedform.
 5. The process according to claim 1, wherein the active compound(I) suspended in the granulating liquid is introduced into the moistgranulation.
 6. The process according to claim 1, wherein the resultingpharmaceutical composition is a tablet rapidly releasing the activecompound (I).
 7. Solid, orally administrable pharmaceutical compositionprepared by the process according to claim
 1. 8. Solid, orallyadministrable pharmaceutical composition, comprising5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidin-5-yl}-methyl)-2-thiophene-carboxamide(I) in hydrophilized form.
 9. Pharmaceutical composition according toclaim 8, comprising the active compound (I) in crystalline form. 10.Pharmaceutical composition according to claim 9, comprising the activecompound (I) in micronized form.
 11. The pharmaceutical compositionaccording to claim 7, wherein the active compound (I) is present in aconcentration of 1 to 60% based on the total mass of the formulation.12. The pharmaceutical composition according to claim 7, furthercomprising sodium lauryl sulphate as a wetting agent.
 13. Thepharmaceutical composition according to claim 12, comprising sodiumlauryl sulphate in a concentration of 0.1 to 5%, based on the totalmass.
 14. The pharmaceutical composition according to claim 7, furthercomprising hydroxypropylmethylcellulose as a hydrophilic binding agent.15. The pharmaceutical composition according to claim 14, comprisinghydroxypropylmethylcellulose in a concentration of 1 to 15%, based onthe total mass.
 16. The pharmaceutical composition according to claim 7in the form of a tablet.
 17. The pharmaceutical composition according toclaim 16 in the form of a rapid-release tablet.
 18. The pharmaceuticalcomposition according to claim 16, characterized in that the tablet iscovered with a coating.
 19. A method for the prophylaxis and/ortreatment of thromboembolic diseases comprising administering aneffective amount of the pharmaceutical composition of claim
 7. 20. Amethod for the prophylaxis and/or treatment of thromboembolic diseasescomprising administering an effective amount of5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidin-5-yl}-methyl)-2-thiophenecarboxamide(I) in hydrophilized form.
 21. (canceled)